Sudden cardiac death generally occurs when arrhythmias develop in the ischemic heart. These lethal arrhythmias can arise from alterations in Ca fluxes across the sarcolemma (SL) and possibly the subsarcolemmal cisternae of the sarcoplasmic reticulum (SR). The mechanisms which control Ca fluxes in the heart will be examined in cardiac membrane preparations studied in vitro. Initially SR preparations will be used. The actions of inhibitors of the slow inward current on ATP-dependent Ca transport in cardiac SR will be studied, as will their effects on carrier-mediated Ca efflux. The mechanisms of action of these agents, including potential agents for the prevention of sudden cardiac death, in the reaction mechanism responsible for Ca transport by the SR will be examined and the role of the Ca-transport ATPase and low molecular weight SR proteins in regulating calcium fluxes will be evaluated. In view of the importance of catecholamines in provoking sudden cardiac death, the ability of a phosphoprotein formed by cyclic AMP-dependent protein kinases to accelerate Ca-transport in the SR will be examined. The properties and functional significance of the phosphoprotein phosphatase and adenylate cyclase activities found in SR preparations will be evaluated. A protocol in which the electrophysiological effects of antiarrhythmic drugs will be compared in normal and ischemic myocardium will provide a basis for examining the significance of data obtained from studies of cell organelles in vitro in terms of their role in producing electrophysiological alterations responsible for lethal arrhythmias. These studies of a model of lethal arrhythmias in the hearts of experimental animals also will permit evaluation of the usefulness of new drugs and approaches to therapy in terms of future use in patients with ischemic heart disease at risk of sudden cardiac death.